mal human cells in culture, telomere shortening and instability is a natural feature of replicative cell senescence (Harley and Villeponteau 1995; Bacchetti 1996). In often degenerate forms, telomeric repeats are also found in subtelomeric and interstitial chromosomal locations, and there is some evidence that these loci may act as sites at which radiation-induced and other forms of genomic damage are preferentially resolved (Bouffler 1998).

Early studies of the postirradiation development of chromosomal instability in in vitro passaged human diploid fibroblasts were suggestive of instability effects in a high proportion of irradiated cells (Sabatier and others 1992). However, subsequent detailed cytogenetic analyses suggested that passage-dependent instability in cultured human fibroblasts primarily takes the form of telomeric events expressed in cell clones naturally selected by growth rate during passage (Ducray and others 1999). Overall, the data obtained may be interpreted as initial radiation exposure bringing forward in time the natural process of clonal telomeric sequence instability associated with cell senescence and telomere shortening.

A different form of postirradiation telomere-associated instability is expressed in a hamster-human hybrid cell system (Marder and Morgan 1993) where, in some clones, chromosomal instability is persistently expressed at translocations that have telomeric sequences at their junction (Day and others 1998). Similarly, unstable structures have been observed in unirradiated hamster cells undergoing gene amplification (Bertoni and others 1994), and again it may be that radiation is inducing genomic structures that enhance the natural expression of instability.

There is good evidence that telomeric sequence instability is a recurrent feature of tumorigenic development (Bacchetti 1996; Chang and others 2001; Murnane and Sabatier 2004). Of particular relevance to the question of unstable translocation junctions are the so-called segmental jumping translocations that have been well characterized in spontaneously arising human leukemias (Shippey and others 1990). In respect of radiation tumorigenesis, detailed cytogenetic analyses suggest an excess of complex aberrations and segmental jumping translocations in myeloid leukemias arising at old ages in high-dose-exposed atomic bomb survivors (Nakanishi and others 1999). These and other data on excess microsatellite instability in A-bomb myeloid leukemias (Nakanishi and others 2001) have been reanalyzed in respect of dose and probability of tumor causation (Cox and Edwards 2002; Little 2002). These reanalyses largely uncouple the expression of leukemia-associated jumping translocations and microsatellite instability from radiation causation and argue that the potential contribution of induced instability to leukemogenic risk is likely to be small.

Telomeric sequence instability at radiation-associated deletion or translocation breakpoints in mouse myeloid leukemia has also been recorded; this is not a general characteristic of these tumor-associated events, and recent studies argue against the direct involvement of telomeric sequence instability in these events (Bouffler and others 1996; Finnon and others 2002).

In conclusion, although the position regarding radiation-induced persistent genomic instability and its causal association with tumorigenesis is not well understood, a few specific points can be made:

In the case of radiation-associated persistent telomeric rearrangement and unstable chromosome translocation junctions, a coherent case can be made that a certain fraction of misrepaired genomic damage after radiation may be prone to ongoing secondary change in clonal progeny. There is evidence that such secondary genomic rearrangement can be a normal component of tumor development, in which case it is reasonable to assume that excess instability of this type could be a feature of some radiation-associated tumors, particularly those arising after high-dose irradiation where multiple or complex rearrangements may be expected.

The genetic evidence from mouse studies that postirradiation chromatid instability can be associated with mammary tumor development is also persuasive, although it leaves unanswered questions on the causal role of the excess chromatid damage observed in vitro. Thus, in certain genetic settings of DNA repair deficiency, a role for postirradiation chromatid instability in tumorigenesis appears reasonable, and the potential linkage with telomere dysfunction could also be important.

Based on the negative or inconsistent data on in vivo induced genomic instability in bone marrow cells, the nonsharing of genetic determinants, and the contention on data regarding A-bomb leukemias, induced genomic instability is judged unlikely to impact appreciably on the risk of lymphohematopoietic tumors after low-dose radiation.

There are very few data on radiation-associated human solid tumors from which to assess the potential contribution of induced genomic instability. The central problem is the inherent difficulty in distinguishing this specific radiation-induced phenotype from spontaneously developing genomic instability as a natural consequence of clonal selection during tumor development. Stated simply, does tumor instability correlate with initial radiation damage or with neoplastic phenotype?

This problem is well evidenced by molecular studies on post-Chernobyl (Belarus) childhood thyroid cancer. Initial studies showed evidence of excess microsatellite alterations in these radiation-associated tumors when compared with a reference group of adult thyroid cancers (Richter and others 1999). However, more detailed follow-up studies showed that the principal correlation was between microsatellite alterations and the aggression of early arising tumors. When this factor was taken into account, microsatellite loss or mutation in the early Belarus tumors was shown to be similar to that of the adult reference cases (Lohrer and others 2001).

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